6ZA4

M. tuberculosis salicylate synthase MbtI in complex with 5-(3-cyanophenyl)furan-2-carboxylate

Summary for 6ZA4

• Entry DOI: 10.2210/pdb6za4/pdb
• Descriptor: Salicylate synthase, 5-(3-cyanophenyl)furan-2-carboxylic acid, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: salicylate, isochorismate, chorismate, mycobactins, lyase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 4
• Total formula weight: 196913.95

Authors

Mori, M.,Villa, S.,Meneghetti, F.,Bellinzoni, M. (deposition date: 2020-06-04, release date: 2020-07-01, Last modification date: 2024-01-24)

Primary citation

Mori, M.,Stelitano, G.,Gelain, A.,Pini, E.,Chiarelli, L.R.,Sammartino, J.C.,Poli, G.,Tuccinardi, T.,Beretta, G.,Porta, A.,Bellinzoni, M.,Villa, S.,Meneghetti, F.
Shedding X-ray Light on the Role of Magnesium in the Activity ofMycobacterium tuberculosisSalicylate Synthase (MbtI) for Drug Design.
J.Med.Chem., 63:7066-7080, 2020

PubMed Abstract: The Mg-dependent salicylate synthase (MbtI) is a key enzyme involved in the biosynthesis of siderophores. Because iron is essential for the survival and pathogenicity of the microorganism, this protein constitutes an attractive target for antitubercular therapy, also considering the absence of homologous enzymes in mammals. An extension of the structure-activity relationships of our furan-based candidates allowed us to disclose the most potent competitive inhibitor known to date (, = 4 μM), which also proved effective on mycobacterial cultures. By structural studies, we characterized its unexpected Mg-independent binding mode. We also investigated the role of the Mg cofactor in catalysis, analyzing the first crystal structure of the MbtI-Mg-salicylate ternary complex. Overall, these results pave the way for the development of novel antituberculars through the rational design of improved MbtI inhibitors.

PubMed: 32530281
DOI: 10.1021/acs.jmedchem.0c00373

Experimental method

X-RAY DIFFRACTION (2.092 Å)